During the past several decades, an increased incidence of papillary thyroid cancer has been reported in many parts of the world, including the United States, with unknown reasons. Emerging evidence indicates that polybrominated diphenyl ethers (PBDEs) and other polyhalogenated aromatic hydrocarbons (PHAHs), including polychlorinated biphenyls (PCBs) and organochlorine pesticides, are able to alter thyroid hormone homeostasis and cause thyroid dysfunction. These changes are suspected to lead to tumorigenesis of the thyroid gland. While animal studies have provided solid evidence in support of the link between PHAHs and thyroid cancer risk, no human studies have been conducted to test this novel hypothesis that exposure to PBDEs and other PHAHs increases the risk of papillary thyroid cancer. Here, we propose a case-control study nested in a large US military cohort to examine 1) the association between PBDE/PHAH exposure and papillary thyroid cancer risk; 2) the association between PBDE/PHAH exposure and thyroid hormone disruption; and 3) whether the risk of papillary thyroid cancer and thyroid hormone disruption associated with environmental exposure to PHAHs varies by genetic polymorphisms in major genes coding for enzymes involved in the regulation, metabolism, or functional activities of PHAHs and endogenous thyroid hormones. The proposed study will be conducted using PRE-DIAGNOSTIC sera from the Department of Defense Serum Repository (DoDSR), which contains over 44 million serum specimens collected from over 9 million people since 1989. Cases will be ascertained via a centralized military tumor registry. The study will include 800 incident cases of papillary thyroid cancer that were diagnosed between 2000 and 2012 with pre-diagnostic sera banked in the DoDSR. One control will be matched to each case based on age, gender, and the date of serum draw. Data on potential confounders, including age, weight and height, sex, and race, will be available for each subject through linkage with military healthcare and administrative databases. Results from the study will not only advance our knowledge of the poorly understood etiology of papillary thyroid cancer, but also provide important scientific evidence to policy makers who regulate the production and use of these compounds and will intrigue other research areas to figure out ways to eliminate the existing sources of PBDEs and other PHAHs. PUBLIC HEALTH RELEVANCE: The increasing incidence of papillary thyroid cancer, and increased human exposure to polybrominated diphenyl ethers (PBDEs) and other polyhalogenated aromatic hydrocarbons (PHAHs) among the general population, makes understanding the relationship between PBDEs and other PHAHs and risk of papillary thyroid cancer a public health priority.